title: Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: hints for collateral sensitivity.
abstract: With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3,4-tetrahydroisoquinoline (15) and 9-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-9H-carbazole (25) showing exceptional selectivity for the σ2 subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin-resistant MCF7adr cell line. Surprisingly, a few compounds, including 25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug-resistant tumors. All of the compounds showed interaction with P-glycoprotein (P-gp), and 15 and 25, with the greatest activity, were able to revert P-gp-mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug- resistant cancers.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, 70125 Bari (Italy).
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005452:Fluoresceins; D017480:Receptors, sigma; C106107:sigma-2 receptor; C085925:calcein AM; D004317:Doxorubicin
keywords: antitumor agents; breast cancer; collateral sensitivity; multidrug resistance; sigma receptors